Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo

Human Medical Genetics Program, School of Medicine, University of Colorado, P.O. Box 6511, Mailstop 8300, Aurora, CO 80045, USA.
New England Journal of Medicine (Impact Factor: 55.87). 05/2010; 362(18):1686-97. DOI: 10.1056/NEJMoa0908547
Source: PubMed


Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.
To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.
We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.
We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

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Available from: Elizabeth Helen Kemp, Oct 01, 2015
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    • "The presentation is mediated by HLA class I molecules, principally by HLA-A*0201 which itself is a major risk allele of generalized vitiligo. HLA-A*0201 and TYR 402Arg genes show an important genetic interaction conducive to the occurrence of vitiligo susceptibility which is reflected by biological interaction [51]. TYR 402Gln variant encodes unstable polypeptide stored and degraded within the endoplasmic reticulum. "
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    ABSTRACT: Vitiligo is a common acquired depigmentation disorder of the skin manifested by the presence of white macules. The disease occurs at a frequency of approximately 1-4% of the world population. Currently, the most popular theory of vitiligo development is a multifactorial hypothesis according to which genetic conditions predispose vitiligo macules to occur as a result of specific environmental factors. According to the genetic hypothesis, vitiligo inheritance is multigenic. Genetic studies conducted so far concern patients with non-segmental vitiligo. There are three basic techniques of genetic studies: candidate gene association studies, genomewide linkage studies and genome-wide association studies (GWAS). The GWAS are the "gold standard" for detecting susceptibility genes. Up to now, approximately 36 convincing non-segmental vitiligo susceptibility loci have been identified. Approximately 90% of them encode immunoregulatory proteins, while approximately 10% encode melanocyte proteins. The existence of various associations between vitiligo and other autoimmune diseases may provide new knowledge on the causes of many disorders. Examples include the inverse relationship between vitiligo and melanoma and association of vitiligo with other autoimmune diseases. The main goal of all researches is to find new, optimal therapeutic strategies for vitiligo and other autoimmune diseases.
    Postepy Dermatologii I Alergologii 08/2014; 31(4):247-55. DOI:10.5114/pdia.2014.43497 · 0.85 Impact Factor
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    • "KP in vitiligo can be used as a clinical parameter predicting prognosis24. Although the pathogenesis of KP in vitiligo remains unclear, multiple factors induced by trauma might be associated with the aggravation of vitiligo, including inflammatory cytokines, increased oxidative stress, defective melanocyte adhesion, and melanocyte growth factors5,11,25,26,27. Although occupations associated with frequent mechanical trauma among enrolled patients were not specifically reported in our study, in univariate analysis patients working in production or mining/manufacturing, which could be expected to have frequent mechanical trauma, more commonly reported that their workplace environment affected the development of vitiligo, as compared with vitiligo patients that had other jobs. "
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    ABSTRACT: BackgroundIt was previously thought that persons with genetic predispositions to vitiligo develop the condition after exposure to various precipitating environmental factors. However, in many cases, the aggravating factors of vitiligo have not been clearly identified.ObjectiveTo identify the aggravating factors of vitiligo in the working environment and daily life.MethodsA total of 489 vitiligo patients were recruited from 10 institutions in South Korea; patients were provided with a questionnaire about environmental factors and behavior patterns in the workplace and in daily life, and their association with vitiligo.ResultsNinety-five of the 470 enrolled patients (20.2%) answered that environmental risk factors in daily life and in the workplace affected the development of vitiligo. The most frequently attributed causes were trauma and burn (13.6%), followed by sunlight (12.8%), stress (12.8%), cleaning products/disinfectant/chemicals (4.9%), and hair dye (2.1%).ConclusionVitiligo of the hand and foot was associated with frequent exposure to aggravating materials and overexposure to sunlight, along with frequent trauma of these areas, all of which could be considered important risk factors of vitiligo. The development of vitiligo could potentially be controlled through the early detection of aggravating factors.
    Annals of Dermatology 06/2014; 26(3):349-56. DOI:10.5021/ad.2014.26.3.349 · 1.39 Impact Factor
    • "The most important recent developments in vitiligo occurred in two large-scale genome wide association studies of generalized vitiligo, one in Caucasians[10] and the other in Chinese,[11] which together identified and confirmed at least 16 different loci that contribute to the susceptibility of generalized vitiligo. "
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    ABSTRACT: Epidemiological studies have shown that vitiligo is a complex trait, involving combinations of pathogenic effects of multiple susceptibility genes as well as environmental risk factors. To observe whether consanguinity increased the incidence of vitiligo in Saudi patients from Arar. This study included 69 Saudi patients with vitiligo and their families. These patients, selected from the experience specialist dermatology center in Arar, from April 2011 to 2012, were interviewed by a dermatologist to confirm the diagnosis and complete a questionnaire. A total of 69 patients, 40 males and 29 females were selected. Their mean age was 34.5 ± 11.8 years with the median age of 23 years. The mean age at onset of disease was 27.9 ± 12.9 years. The mean duration of the disease was 9.7 ± 5.3 years. The frequency of focal, vulgaris, universal, and acrofacial subtypes was 22 (31.9%), 21 (30.4%), 8 (11.6%), and 18 (26.1%), respectively. A positive family history of vitiligo was obtained in 45 (65.2%) cases. A comparison of the frequency of vitiligo among siblings in relation to the general population was more in accord with the multifactorial model. Consanguinity in marriage increases the incidence of the disease. Therefore, genetic counseling and premarital examination would be important contributions to lower the prevalence of vitiligo.
    03/2014; 21(1):13-6. DOI:10.4103/2230-8229.128767
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